Cancer refers to a cluster of cells showing overproliferation by non-coordination of the growth and proliferation of cells due to the loss of the differentiation ability of cells Most cancers occur by multistep carcinogenesis that the mutation of oncogenes and tumor suppressor genes occurs throughout 5˜8 stages and finally cancer cells are generated. It has been known that activation of oncogenes inducing a cancer induces abnormal proliferation of cells and activation of tumor suppressor genes suppresses such abnormal proliferation of cells and blocks generation of cancer cells by killing specific cells by the activation of cell death program.
Until now, as genes associated with generation of cancer, there have been found 100 or more genes. Typical oncogenes include H-ras, N-ras, K-ras, c-myc and N-myc genes. These oncogenes are distributed throughout almost all the chromosomes in humans, and the mutation of these genes gives rise to abnormal proliferation of cells, which are then developed into cancer cells. Of them, the overexpression of c-myc was observed in various cancers in humans, for example, 80% of breast cancer, 70% of colon cancer, 90% of gynecological cancer and 50% of hepatocellular cancer. Besides, the abnormal overexpression of c-myc is known to be associated with blood tumor, cervical cancer, lung cancer, small cell lung cancer, stomach cancer, gonadal cancer, colon cancer, adenocarcinoma, promyelocyte leukemia, desmoplastic fibroblastoma, squamous cell carcinoma, myelocytoma and so on.
As typical tumor suppressor genes suppressing abnormal proliferation of cells, there can be mentioned p53, p16, p21, p24 and p27. The tumor suppressor genes suppress abnormal division and proliferation of cells and also, they have a function of repairing cellular DNAs when they are injured and have been known to be associated with regulation of apoptosis and proliferation of cells to prevent DNA from being amplified without limit.
Attempts to treat cancers using the oncogenes and tumor suppressor genes that have been recently identified are being under active progress. That is, various gene therapy including inhibition of the activity of oncogenes by developing compounds capable of downregulating the overexpressed oncogenes and by developing antisense genes against the oncogene, or in vivo replacement of the injured oncogenes by normal genes have been attempted. In addition, factors inducing the apoptosis of cancer cells have been developed in various manners as anticancer agents.
Meanwhile, p38/JTV-1 has been known as an auxiliary factor of aminoacyl-tRNA synthetases (ARSs) protein complex in higher eukaryotes (Quevillon S. et al., J. Mol. Biol., 285; 183–195, 1999). Since the ARSs are enzymes catalyzing ligation of specific amino acid to their cognate tRNA, p3/JTV-1 is assumed to have a function associated with synthesis of proteins Besides, the gene coding for p38/JTV-1 is located in human chromosome 7 and arranged in a head to bead fashion with the gene coding for PMS2 that is involved in mismatch DNA repair (Kolodner R. D. et al., Curr. Opin. Gene. Dev, 9:89–96, 1999) The p38/JTV-1 protein that is coded by the p38/JTV-1 gene comprises 320 amino acid residues in mouse and comprises 312 amino acid residues in human, and their sequences have been known (Quevillon S. et al., J. Mol. Biol., 285:183–195, 1999). The p38/JTV-1 protein is a hydrophobic protein and is assumed to contain leucine-zipper motif, which is a region associated with protein-protein interaction (Quevillon S. et al., J Mol. Biol. 8:285(1), 183–95, 1999) The p38/JTV-1 was also reported as another name, JTV-1 protein (Nicolaides et al., Genomics, 29:329–334, 1995). However, so far the exact functions of p38/JTV-1 have not been known.
The inventors of the present invention found that in the course of conducting the experiments to identify, the functions of p38/JTV-1, the p38/JTV-1 bound to the FBP (FUSE binding protein) that promotes the transcription of c-myc and bound to the PDK-1 (phosphoinositide-dependent kinase) in the AKT-P13K pathway of regulating apoptosis. Based on such findings, the inventors identified that the p38/JTV-1 has new activities of suppressing the proliferation of cells by downregulating c-myc through the interaction with FBP and of promoting apoptosis by suppressing phosphorylation of AKT (serin/threonine kinase) through the interaction with PDK-1 and also identified that the p38/JTV-1 could be useful as a tumor suppressor by virtue of such characteristics and accordingly, the inventors have completed the subject invention.